Deep vein thrombosis in upper extremities: Clinical characteristics, management strategies and long-term outcomes from the COMMAND VTE Registry

doi:10.1016/j.thromres.2019.02.029

Thrombosis Research

Volume 177, May 2019, Pages 1-9

https://doi.org/10.1016/j.thromres.2019.02.029 Get rights and content

Highlights

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Deep vein thrombosis (DVT) patients in upper extremities accounted for 3.0%
•
They more often had active cancer and central venous catheter use at diagnosis.
•
They less often had concomitant pulmonary embolism at diagnosis.
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They had similar long-term risk for recurrence as those in lower extremities.

Abstract

Introduction

There is a paucity of data on patients with deep vein thrombosis (DVT) in upper extremities.

Materials and methods

The COMMAND VTE Registry is a retrospective multicenter registry enrolling 3027 consecutive patients with acute symptomatic venous thromboembolism (VTE) in Japan. The current study population included 2498 patients with upper or lower extremities DVT.

Results

There were 74 patients (3.0%) with upper extremities DVT and 2424 patients with lower extremities DVT. Patients with upper extremities DVT more often had active cancer (58%) and central venous catheter use (22%). The proportion of concomitant pulmonary embolism at diagnosis was lower in patients with upper extremities DVT than in those with lower extremities DVT (14% and 51%, P < 0.001). Discontinuation of anticoagulation therapy was more frequent in patients with upper extremities DVT (63.8% and 29.8% at 1-year, P < 0.001). The cumulative 3-year incidence of recurrent VTE was not different between the 2 groups (9.8% and 7.4%, P = 0.43). After adjusting confounders, the risks of upper extremities DVT relative to lower extremities DVT for recurrent VTE remained insignificant (HR 0.94, 95%CI 0.36–2.01, P = 0.89).

Conclusions

The prevalence of patients with DVT in upper extremities was 3.0% in the current large-scale real-world registry. Patients with DVT in upper extremities more often had active cancer at diagnosis and central venous catheter use as a transient risk factor for VTE, and less often had concomitant PE. Patients with DVT in upper extremities had similar long-term risk for recurrent VTE as those with DVT in lower extremities despite shorter duration of anticoagulation.

Introduction

Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), is a major health problem in the world [1,2]. PE is caused by blockage of pulmonary arteries by thrombus, which is developed in veins and travels through the blood stream. The sources of thrombus are thought to be mostly veins in lower extremities, whereas DVT in upper extremities, which usually refers to thrombosis of the axillary or subclavian veins, rarely occurs spontaneously and sometimes develops as a complication of central venous catheter placement or cancer [3,4]. Historically, DVT in upper extremities was considered as a rare self-limited disease [5,6]. However, recent studies reported that DVT in upper extremities might have significant complications, including PE, loss of vascular access, superior vena cava syndrome, and post-thrombotic syndrome [7,8]. Furthermore, DVT in upper extremities could be increasing, due to widespread use of central venous catheters and increase in cancer survivors.

To date, no randomized controlled trials have evaluated treatment strategies of patients with DVT in upper extremities, leading to uncertainty in optimal treatment strategies including anticoagulation therapy. Furthermore, few studies have evaluated long-term clinical outcomes of patients with DVT in upper extremities. Therefore, we sought to evaluate the clinical characteristics, management strategies, and long-term outcomes of patients with DVT in upper extremities in a large observational database in Japan.

Section snippets

Study population

The COMMAND VTE (COntemporary ManageMent AND outcomes in patients with Venous ThromboEmbolism) registry is a physician-initiated, retrospective, multicenter cohort study enrolling consecutive patients with acute symptomatic VTE objectively confirmed by imaging examinations (ultrasound, contrast-enhanced computed tomography (CT), ventilation-perfusion lung scintigraphy, pulmonary angiography, or contrast venography) or by autopsy among 29 centers in Japan between January 2010 and August 2014.

Patient characteristics

In the entire study population, the mean age was 67 years, 61% were women, and mean body weight and body mass index were 57.6 kg and 23.1 kg/m², respectively. There were 74 patients (3.0%) with DVT in upper extremities and 2424 patients (97%) with DVT in lower extremities. The baseline patient characteristics were different in several aspects between the 2 groups (Table 1). Patients with DVT in upper extremities were younger, more often had active cancer at diagnosis and central venous catheter

Discussion

The main findings of the current study were as follows; 1) Among patients with DVT in upper or lower extremities, the prevalence of patients with DVT in upper extremities was 3.0%; 2) Patients with DVT in upper extremities more often had central venous catheter placement and active cancer, and less often had concomitant PE; and 3) The risk for recurrent VTE was not significantly different between patients with DVT in upper extremities and those in lower extremities.

DVT in upper extremities is a

Study limitations

The current study has several limitations. First and most importantly, the absolute number of patients with DVT in upper extremities was small (N = 74), although it was derived in a large observational database of patients with VTE. Due to lack of adequate statistical power, we could not conduct detailed analyses among patients with DVT in upper extremities. Therefore, the results of the current study should be regarded as exploratory and hypothesis generating. Especially, as for major

Conclusions

Acknowledgements

We appreciate the support and collaboration of the co-investigators participating in the COMMAND VTE Registry. We are indebted to the independent clinical research organization (Research Institute for Production Development, Kyoto, Japan) for technical support.

Conflicts of interest

Dr. Yamashita received lecture fees from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, and Bayer Healthcare. Dr. Morimoto received lecture fees from Mitsubishi Tanabe Pharma and Pfizer Japan and consultant fees from Asahi Kasei, Bristol-Myers Squibb, and Boston Scientific. Dr. Akao received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare and Daiichi-Sankyo. Dr. Kimura serves as an advisory board member for Abbott Vascular and Terumo Company. All other

Funding

The COMMAND VTE Registry is supported by the independent clinical research organization (Research Institute for Production Development, Kyoto, Japan) and research funding from Mitsubishi Tanabe Pharma Corporation. The research funding had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

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Data on complications after upper extremity vein thrombosis (UEVT) are limited and heterogeneous.
The aim of the present study was to evaluate the pooled proportions of venous thromboembolism (VTE) recurrence, bleeding, and post-thrombotic syndrome (PTS) in patients with UEVT. A systematic literature review was conducted of PubMed, Embase, and the Cochrane Library databases from January 2000 to April 2023 in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. All studies included patients with UEVT and were published in English. Meta-analyses of VTE recurrence, bleeding, and of PTS after UEVT were performed to compute pooled estimates and associated 95% confidence intervals (CIs). Subgroup analyses of cancer-associated UEVT and catheter-associated venous thrombosis were conducted. Patients with Paget-Schroetter syndrome or effort thrombosis were excluded.
A total of 55 studies with 15,694 patients were included. The pooled proportions for VTE recurrence, major bleeding, and PTS were 4.8% (95% CI, 3.8%-6.2%), 3.0% (95% CI, 2.2%-4.0%), and 23.8% (95% CI, 17.0%-32.3%), respectively. The pooled proportion of VTE recurrence was 2.7% (95% CI, 1.6%-4.6%) for patients treated with direct oral anticoagulants (DOACs), 1.7% (95% CI, 0.8%-3.7%) for patients treated with low-molecular-weight heparin (LMWH), and 4.4% (95% CI, 1.5%-11.8%) for vitamin K antagonists (VKAs; P = .36). The pooled proportion was 6.3% (95% CI, 4.3%-9.1%) for cancer patients compared with 3.1% (95% CI, 2.1%-4.6%) for patients without cancer (P = .01). The pooled proportion of major bleeding for patients treated with DOACs, LMWH, and VKAs, was 2.1% (95% CI, 0.9%-5.1%), 3.2% (95% CI, 1.4%-7.2%), and 3.4% (95% CI, 1.4%-8.4%), respectively (P = .72). The pooled proportion of PTS for patients treated with DOACs, LMWH, and VKAs was 11.8% (95% CI, 6.5%-20.6%), 27.9% (95% CI, 20.9%-36.2%), and 24.5% (95% CI, 17.6%-33.1%), respectively (P = .02).
The results from this study suggest that UEVT is associated with significant rates of PTS and VTE recurrence. Treatment with DOACs might be associated with lower PTS rates than treatment with other anticoagulants.
The clinical topography of peripherally inserted central catheter-related thrombosis in cancer patients: A prospective and longitudinal observational study based on ultrasound scans every two days
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To delineate the clinical topography of peripherally inserted central catheter (PICC)-related thrombosis in cancer patients.
Most of the clinical features of PICC-related thrombosis are based on a single follow-up, which is insufficient to reflect the full topography of a thrombosis.
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Cancer patients scheduled for PICC placement were potentially eligible; patients with contraindications to PICC placement or existing diseases affecting blood flow were excluded; and those who later withdrew or did not reply to our contact request during the follow-up period were eliminated from this study. Ultrasound was used to detect thrombosis from the insertion site, proximal insertion site, axillary vein to the subclavian vein once every two days for two weeks post insertion. The thrombosis and its involved venous segments, onset time and symptoms and signs were recorded.
Among the 173 included patients, 126 (72.8 %) were identified as having thrombosis. Specifically, 113 and 126 patients were identified as having thrombosis within the first three days and the first week post insertion, respectively. In the 126 patients, thrombosis occurred at the insertion site (72.8 %) concurrently with thrombosis at the proximal insertion site (n = 120, 69.4 %), thrombosis in the axillary vein (n = 94, 54.3 %), and/or thrombosis in the subclavian vein (n = 41, 23.7 %). The log-rank test demonstrated that thrombosis in these four venous segments decreased significantly from the distal to the proximal central vein (log-rank test = 117.128, P < .001). Of 31 patients (17.9 %) who presented symptomatic thrombosis, only five patients experienced obvious swelling in the upper arm, and the other 26 patients exhibited atypical symptoms, such as soreness, tightness, numbness, tingling, or other discomforts in the palm, arm, armpit, and/or shoulder. In some thrombotic cases, ultrasonic assessment of PICC-related thrombosis did not parallel clinical symptoms and signs.
PICC-related thrombosis is common and can occur very early post insertion in cancer patients, and most thromboses present atypical symptoms. More than half of the cases with thrombosis evaluated involve multiple venous segments, and the farther the venous segments are from the central vein, the higher the incidence of thrombosis tend to be and the earlier the onset time are.
The results highlight the importance that medical staff pay particular attention to patients with catheters in the first week post insertion and be alert to thrombosis presenting atypical symptoms while keeping in mind that clinical symptoms and signs are not reliable for diagnosing thrombosis.
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In the 94% of patients who were followed for a mean of 29 months after DOAC discontinuation, recurrent VTE was 3.0 per 100 patient-year; nearly 60% of these events were recurrent ipsilateral UEDVTs. Data from two recent international registries showed a 3% and 4% prevalence of UEDVT in the general population of patients with DVTs [6,20]. Compared to patients with lower extremities DVT, those with UEDVT were significantly more likely to have a central venous catheter (11.5% vs. 0.5%), or active cancer (16.2% vs 8.7%).
Limited data are available on the role of direct oral anticoagulants (DOACs) for the treatment of upper extremities deep vein thrombosis (UEDVT).
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Overall, 188 patients were included in the study: mean age 52.4 ± 20.4 years, males 43.6%, patients with active cancer 29.2%. Twenty-nine percent of patients had 2 or more risk factors for VTE, 33.0% had catheter-related or pacemaker-related UEDVT. In 13.8% of patients, DOACs were started one month after UEDVT diagnosis or later. Active cancer was an independent predictor for delayed initiation of DOACs (OR 8.1, 95% CI 3.0–22.2). Mean duration of treatment with DOACs was 5.1 ± 2.8 months.
During treatment with DOACs, recurrent VTE occurred in 0.9 per 100 patient-year, major bleeding in 1.7 and all-cause deaths in 6.0 per 100 patient-year. No fatal bleeding or fatal VTE recurrence were observed. During 232.1 patient-years of follow-up after DOAC withdrawal, recurrent VTE occurred in 3.0 per 100 patient-year. The 2019 ESC categories for risk of VTE recurrences were able to discriminate patient groups at different risk of events in the on and off-treatment periods.
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Risk of pulmonary emboli after removal of an upper extremity central catheter associated with a deep vein thrombosis
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Since the primary outcome in this study was a safety end point, the most conservative definition of new PE was used and may be an overestimation. Data from registries have shown that 32% to 41% of UE-DVTs were associated with CVCs, and in cases when they were not, malignancy was a provoking risk factor in 50% of patients.18,19 Therefore, the patient population in this study, active hematologic malignancy with CVCs, may not be generalizable to all CVC-associated UE-DVT.
Standard treatment of catheter-associated upper extremity deep vein thrombosis (UE-DVT) is anticoagulation, although catheters are often removed for this indication. The optimal time for catheter removal and whether the act and/or timing of catheter removal is associated with pulmonary embolism (PE) remain unknown. A retrospective cohort study was performed at 8 participating institutions through the Venous thromboEmbolism Network US. Patients with hematologic malignancies and central venous catheter (CVC)–associated UE-DVT were included from 1 January 2010 through 31 December 2016. The primary outcome was objectively confirmed PE within 7 days of UE-DVT diagnosis in anticoagulated patients comparing early (≤48 hours) vs delayed (>48 hours) catheter removal. A total of 626 patients were included, among whom 480 were treated with anticoagulation. Among anticoagulated patients, 255 underwent early CVC removal, while 225 had delayed or no CVC removal; 146 patients received no anticoagulation, among whom 116 underwent CVC removal alone. PE within 7 days occurred in 2 patients (0.78%) with early removal compared with 1 patient (0.44%) with delayed or no CVC removal (P > .9). PE or any cause of death within 7 days occurred in 3 patients in both the early removal (1.18%) and delayed/no removal (1.33%) groups (P > .9). In patients treated with CVC removal only (no anticoagulation), there were no PEs but 3 deaths within 7 days. In patients with hematological malignancy and CVC-associated UE-DVT, early removal of CVCs was not associated with an increased risk of PE compared with delayed or no removal.
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Presence and catheter type has been associated with risk of upper extremity thrombosis [3–5]. CRT accounts for between 22 and 45% of upper extremity thrombosis, and pulmonary emboli have been detected in 8–15% of patients with symptomatic CRT [1,6–8]. Cancer patients have a 3-fold greater risk of recurrent thrombosis and 2.5 –fold higher risk of major hemorrhage compared to non-cancer patients, emphasizing the delicate balance between bleeding and clotting [9].
Optimal treatment of catheter-related thrombosis (CRT) is uncertain in patients with hematologic malignancy. We aimed to evaluate the treatment strategies, outcomes, and predictors of recurrent venous thromboembolism (VTE) associated with catheter-related thrombosis (CRT) in patients with hematologic malignancy.
We performed a multicenter retrospective cohort study of eight institutions through the Venous thromboEmbolism Network US. Patients with hematologic malignancies with documented CRT were identified using ICD-9 and ICD-10 diagnostic codes. Semi-competing risks proportional hazard regression models were created.
Of the 663 patients in the cohort, 124 (19%) were treated with anticoagulation alone, 388 (58%) were treated with anticoagulation and catheter removal, 119 (18%) treated with catheter removal only, and 32 (5%) had neither catheter removal nor anticoagulation. 100 (15%) patients experienced a recurrent VTE event. In the 579 patients who had catheter removal, the most common reason for catheter removal was the CRT [392 (68%)]. For subjects who received any anticoagulation (n = 512), total anticoagulation duration was not associated with VTE recurrence [1.000 (0.999–1.002)]. After adjustment patients treated with catheter removal only had an increased risk of VTE recurrence [2.50 (1.24–5.07)] and death [4.96 (2.47–9.97)]. Patients with no treatment had increased risk of death [16.81 (6.22–45.38)] and death after VTE recurrence [27.29 (3.13–238.13)].
In this large, multicenter retrospective cohort, we found significant variability in the treatment of CRT in patients with hematologic malignancy. Treatment without anticoagulation was associated with recurrent VTE.

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Full Length ArticleDeep vein thrombosis in upper extremities: Clinical characteristics, management strategies and long-term outcomes from the COMMAND VTE Registry

Highlights

Abstract

Introduction

Materials and methods

Results

Conclusions

Introduction

Section snippets

Study population

Patient characteristics

Discussion

Study limitations

Conclusions

Acknowledgements

Conflicts of interest

Funding

Am. J. Med.

Chest

Am. J. Cardiol.

Lancet

Am. J. Med.

Chest

J. Thromb. Haemost.

Blood

J. Thromb. Haemost.

Chest

The epidemiology of venous thromboembolism

Circulation

Upper extremity thrombosis: etiology and prognosis

Angiology

Consequences of "conservative" conventional management of axillary vein thrombosis

Can. J. Surg.

Full Length Article
Deep vein thrombosis in upper extremities: Clinical characteristics, management strategies and long-term outcomes from the COMMAND VTE Registry